Many bioactive topical agents, such as sunscreens, moisturizers, repellents, antimicrobials, and other pharmaceuticals, are intended for use on the surface of human skin. Such agents are generally effective only as long as the agent persists on the skin. As a result, however, of normal daily activities, for example, perspiring, washing, or wearing clothes, a topical agent loses its activity due to premature removal. Despite recognition of this substantivity problem, i.e., the problem of significantly sustained presence of the topical agent, no satisfactory solution has been proposed in the prior art.
Attempts to prolong substantivity of a topical agent have focused on developing compositions which incorporate excessive amounts of water-insoluble materials. These formulations result in cosmetically undesirable surface coatings and occlusion of the skin, yet do not substantially enhance the substantivity of the bioactive agent. Many commercially available topical formulations consist of an oily carrier of base such as mineral oil or a fatty acid ester, or a polymeric carrier or base such as polymethacrylate or polydimethylsiloxane which is insoluble or nearly insoluble in water, plus a bioactive agent (e.g., an ultraviolet-absorbing or antimicrobial agent). Such compositions tend to be greasy, tacky, occlusive (cause excess perspiration), and also tend to stain clothing. These water-insoluble compositions only provide minimal wash-resistance and do little to control the release of the bioactive agent either off of the skin or into the blood. Alternative attempts to prolong substantivity of topically delivered bioactive agents have focused on developing band aid-like patches. This approach is cosmetically undesirable.
There has been considerable interest in the use of organopolysiloxane compounds as surface agents. Organopolysiloxanes exhibit a broad spectrum of properties depending on molecule size, side-chain group type, and the degree of cross-linking between chains. These polymers, which are predominantly polymethylsiloxanes and polymethylphenylsiloxanes, are generally safer and more resistant to attack by temperature, sun, water, ozone, chemicals, corona discharge, dirt, and shear than their carbon counterparts. As a result, many of these polymers have been used as surface protective agents for inanimate substrates. For example, silicones have been used as insulators in high temperature electric machines, as lubricants for high stress, shear, and temperature environments, and as weather protection and water repellency treatments for masonry, leather, textile, paper, metal, and glass surfaces. See, for example, W. Noll, Chemistry and Technology of Silicones, Chapter 10, Academic Press, 1968.
Fully polymerized siloxane compounds have also been used in the formulation of cosmetics, pharmaceuticals, and artificial implants. General inertness, high performance under stress, and specific ability to retard blood clotting are key qualities of silicone biological implants. In cosmetic and pharmaceutical formulations for skin applications, polysiloxanes are typically used as the carrier (or part of the carrier) to provide a non-greasy, low vapor pressure, inert matrix for the bioactive ingredient. Polysiloxanes have been used, for example, (1) to provide a water-insoluble, low vapor-pressure matrix for insect repellents as described in Kauppi U.S. Pat. No. 2,681,878, issued Jun. 22, 1954 and for skin protectants as described in Morgulis U.S. Pat. No. 2,698,824, issued Jan. 4, 1955; (2) to provide a non-greasy cosmetic formulation as described in Kass U.S. Pat. No. 3,392,040 issued Jul. 9, 1968; (3) to provide a non-tacky cosmetic formulation as described in Clum et al. U.S. Pat. No. 4,423,041 issued Dec. 27, 1983; and (4) to provide a non-irritating matrix for topical agents as described in Starch U.S. Pat. No. 4,311,695, issued Jan. 19, 1982. These preparations involve polymerization of the siloxane compounds prior to skin contact.
Other silicon-based compounds known as silane coupling agents are used as adhesives for bridging dissimilar materials. Methods for preparing silane coupling agents, also called polymerizable silanes and hydrolyzable silanes, and use of such compounds to provide adhesion between dissimilar inanimate materials such as glasses, metals, textiles, and composite polymers, is well known. See, for example, E. P. Plueddmann, Silane Coupling Agents, Plenum Press, 1982.
The use of silane coupling agents with biomaterials is more recent. Enzymes and proteins have been immobilized on silanized glass. See for example, D. E. Leyden and W. Collins, Silylated Surfaces, Gordon and Breach, 1980, pp. 189, 201, 363. The technique typically involves silylation of porous glass using .gamma.-aminopropyltriethoxysilane, i.e., modification of the glass surface with a polymerizable silane, followed by enzyme/protein reaction with the amine of the aminopropyl glass. This provides a means to effect analytical separation and purification of antibodies and enzymes.
Silane coupling agents have also been used along with other polymers to create cross-linked polymer meshes and cages which typically entrap a biogenic agent such as an insecticide or microbiocide. See, for example, Young et al. U.S. Pat. Nos. 4,172,904 issued Oct. 30, 1979; 4,200,664, issued Apr. 29, 1980; 4,500,337, issued Feb. 19, 1985; 4,500,338, issued Feb. 19, 1985; and 4,500,339, issued Feb. 19, 1985. Such physical entrapment using acrylic polymers for skin topicals has also been described. See, for example, Kubik et al. U.S. Pat. No. 4,172,122 issued Oct. 23, 1979 (sunscreens), and Randen U.S. Pat. No. 4,552,755, issued Nov. 12, 1985 (moisturizing compositions).
Sunscreen formulations have been prepared using silane coupling agents which are polymerized prior to skin contact. See, for example, Morehouse U.S. Pat. Nos. 2,929,829, issued Mar. 22, 1960 and 3,068,153, issued Dec. 11, 1962; Bailey et al. U.S. Pat. No. 2,950,986, issued Aug. 30, 1960; and Black U.S. Pat. Nos. 2,973,383, issued Feb. 28, 1961 and 3,068,152, issued Dec. 11, 1962. Typically, these compositions involve the preparation of a silane coupling agent modified with a sunscreen, followed by formulation into a water-containing base. Specific examples include the preparation of two p-aminobenzoic acid (PABA) derivatives (one via amide derivatization of the PABA-amine and one via amide derivatization of the PABA-carboxyl) and one benzophenone derivative (a sulfonic acid salt) that carry the triethoxysiloxane group (a polymerizable oxysilane). These materials are then formulated into an aqueous solution or creme for end use. The method of formulation incorporates substantial amounts of water (and in most cases, heat as well) which causes polymerization of the silane coupling agent prior to use on the skin.
Ideally, a topical agent should possess several characteristics in order for the bioactive agent to work effectively, efficiently, and safely. It should be non-toxic and without side effects, non-irritating, non-greasy, tackless, odorless, invisible, non-staining, easy to apply, and not easily removed by normal activities so it will provide full bioactive functionality for extended time periods (i.e., 1-7 days). The present invention provides topical agents which have these characteristics to a greater extent than many prior preparations.